Abstract
Hypoxia-inducible factors (HIFs) facilitate cellular adaptation to environmental stress such as low oxygen conditions (hypoxia) and consequently promote tumor growth. While HIF-1α functions in cancer progression have been increasingly recognized, the contribution of HIF-2α remains widely unclear despite accumulating reports showing its overexpression in cancer cells. Here, we report that HIF-2α up-regulates the expression of CD70, a cancer-related surface antigen that improves anchorage-independent growth in cancer cells and is associated with poor clinical prognosis, which can be induced via epigenetic modifications mediated by DNMT1. The ablation of CD70 by RNAi led to decreased colony forming efficiency in soft agar. Most strikingly, we identified the emergence of CD70-expressing cells derived from CD70-negative cell lines upon prolonged hypoxia exposure or DNMT1 inhibition, both of which significantly reduced CpG-nucleotide methylations within CD70 promoter region. Interestingly, DNMT1 expression was decreased under hypoxia, which was rescued by HIF-2α knockdown. In addition, the expression of CD70 and colony forming efficiency in soft agar were decreased by knockdown of HIF-2α. These findings indicate that CD70 expression and an aggressive phenotype of cancer cells is driven under hypoxic conditions and mediated by HIF-2α functions and epigenetic modifications. This provides additional insights into the role of HIF-2α in coordinated regulation of stem-like functions and epigenetics that are important for cancer progression and may present additional targets for the development of novel combinatorial therapeutics.
Highlights
The core regulatory mechanisms for oxygen sensing and adaptation to hypoxia have widely been identified in the past decades [1,2,3,4], whereby the hypoxia-inducible factors Hypoxia-inducible factors (HIFs)-1α and HIF-2α that are oxygen-sensitive subunits of transcriptional complexes predominantly mediate the adaptive responses
We have identified a role for HIF-2α in the hypoxic regulation of the cancer marker CD70 that occurs through DNA methylation mediated by DNMT1 and drives cancer cell proliferation
We demonstrated the impact of CD70 expression on anchorage-independent growth in ovarian, lung, brain and kidney cancer cells
Summary
The core regulatory mechanisms for oxygen sensing and adaptation to hypoxia have widely been identified in the past decades [1,2,3,4], whereby the hypoxia-inducible factors HIF-1α and HIF-2α that are oxygen-sensitive subunits of transcriptional complexes predominantly mediate the adaptive responses. Recent reports have implicated HIF-2α function in tumor progression [6, 7] and especially in the regulation of cancer stem cells [8, 9]. Genetic and/or epigenetic alterations generate cellular heterogeneity [10,11,12], which gives rise to subpopulations that develop growth advantage or chemoresistance [13]. Tumor hypoxia and HIFs have been engaged in epigenetic regulations via remodeling of DNA methylation by DNMTs [14, 15] and up-regulation of the Jumonji C (JmjC)-domain containing histone demethylases [16,17,18]. Identifying epigenetic regulations under hypoxia that generate population diversity and elicit cellular aggressiveness may expand our understanding of cancer cell heterogeneity leading to additional avenues for treatment
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